In 1966 he played in the folk-rock band The Factory, with whom he produced the Frank Zappa demo Lightning Rod Man recorded, which was not published until 1993. From The Factory the group The Fraternity of Man, in which George was never a permanent member, but with whom he played developed. He was two months lead singer of the Standells.
In 1968 he joined the Mothers of Invention as a replacement for Ray Collins on, first as a singer and then he played increasingly rhythm guitar. He is, for example, to listen to Hot Rats. During this time he wrote many songs. Truck Stop Girl, a song from this period was covered, among others, by the Byrds. Thus he got a record deal with Warner Brothers. In 1969, his band Little Feat, named after a remark by Jimmy Carl Black about Georges foot size. The band was very popular in the 1970s and got very good reviews, especially thanks to Georges vocals and slide guitar playing. In between, George was working as a studio musician, for example, Maria Muldaur, Robert Palmer, Linda Ronstadt, John Sebastian, Bonnie Raitt, Mick Taylor, Bill Wyman, Jackson Browne and James Taylor. In 1977 he had to undergo treatment for addiction to kick his cocaine addiction.
1978 George was a producer of the album Shakedown Street by Grateful Dead. In 1979 he returned to Little Feat 's back, to devote himself to a solo career. In the same year appeared his only solo album Thanks I'll Eat It Here, with whom he still went on tour.
On June 29, 1979, suffering from hepatitis and severe overweight Lowell George died in Arlington, Virginia on a heart attack. His ashes were scattered into the sea.
In 1997, the Lowell George Tribute Album Rock & Roll Doctor appeared, on which, among other Bonnie Raitt, Little Feat, Taj Mahal, Randy Newman and Jackson Browne play.